Description of the condition
Intrauterine adhesions (IUAs) are fibrous strings at opposing walls of the uterus. The spectrum of severity of IUAs ranges from minimal to the complete obliteration of the uterine cavity. Any trauma to the endometrium (the inner layer of the uterus) may lead to the formation of de novo IUAs; and nearly 90% of all cases of IUAs are associated with postpartum or postabortion dilatation and curettage (Nappi 2007). The etiological role of infection in the formation of IUAs is, with the exception of genital tuberculosis, controversial (Deans 2010). IUA formation is the major long-term complication of hysteroscopic surgery in women of reproductive age. A randomized controlled trial reports the incidence of postsurgical IUAs at second look hysteroscopy as 3.6% after polypectomy, 6.7% after resection of uterine septa, 31.3% after removal of a solitary myoma and 45.5% after resection of multiple myomas (Taskin 2000). The mechanisms of tissue repair in the human endometrium are poorly understood (Revaux 2008) despite several hypotheses on the origin of cells for endometrial regeneration (Okulicz 2002). Endometrial stem or progenitor cells, present in the human and rodents, may have an important function in endometrial regeneration in normal menstrual cycles and after delivery; this holds promise for new treatments for subfertility associated with IUAs or Asherman's syndrome (Deane 2013). The duration of the endometrial wound healing differs according to the type of pathology as concluded by Yang and co-workers in a prospective cohort study of 163 women undergoing operative hysteroscopy (Yang 2013); the authors reported that the time needed for a complete recovery of the endometrium ranges from one to three months following the hysteroscopic removal of endometrial polyps and submucous fibroids respectively.
IUAs are associated with a poor reproductive outcome. Firstly this is due to infertility with a prevalence as high as 43% (922 of 2151 women) according to a large review of observational studies (Schenker 1982). Secondly, the poor outcome is due to the clinical problem of recurrent miscarriage, ranging from 5% to 39% in women with IUAs according to a review of observational studies (Kodaman 2007). Thirdly, it is due to major and at times devastating obstetric complications, for example placenta accreta or increta and higher risks for preterm delivery, uterine rupture and peripartum hysterectomy as the endpoint of the successful hysteroscopic treatment of severe IUAs (Deans 2010).
Description of the intervention
Several observational studies have suggested different anti-adhesion strategies for preventing de novo adhesion formation following operative hysteroscopy.
Intrauterine contraceptive device or Foley catheter balloon
An intrauterine contraceptive device (IUD) may provide a physical barrier between the uterine walls, separating the endometrial layers after lysis of IUAs. Its insertion as an adjunctive therapy has been recommended in at least 13 observational studies (Deans 2010). The use of a Foley catheter balloon has been reported as an alternative, for similar purposes, in eight observational studies (Deans 2010).
In 1964, Wood and Pena suggested the use of estrogen therapy to stimulate the regeneration of the endometrium after the surgical treatment of IUAs (Wood 1964).
Hyaluronic acid or hyaluronan (HA), is a water soluble polysaccharide. It consists of multiple disaccharide units of glucuronic acid and N-acetylglucosamine bound together by a ß1-3-type glucoside bond. Solutions of HA have visco-elastic properties that have led to interest in developing applications of HA in surgical procedures, for example in ocular surgery and prevention of postsurgical adhesions. However, HA may not be the ideal substance for all procedures due to its limited residence time when applied to a surgical site. It quickly enters the systemic circulation and is then cleared rapidly by catabolic pathways. Attempts to use hyaluronan for preventing postsurgical adhesions have therefore been met with variable success. Chemically modified derivatives of HA have been developed to circumvent the disadvantages of HA. One such derivative is auto-crosslinked polysaccharide (ACP). It is formed by crosslinking hyaluronan via direct formation of covalent ester bonds between hydroxyl and carboxyl groups of the hyaluronan molecule. ACP can be prepared with various degrees of crosslinking, which allows tailoring of the viscosity properties of ACP gels (Renier 2005). Carboxymethylcellulose (CMC) is a high molecular-weight polysaccharide that has a viscosity greater than dextran 70. CMC can be used for adhesion prevention as a membrane barrier or a gel as a mixture of chemically derivative sodium hyaluronate and carboxymethylcellulose gel (HA-CMC) (Leach 1998).
Human amnion membrane grafting
Over the last three decades, the surgical community has become more aware of the increasing potential of human amnion membrane (HAM) as an adjunctive anti-adhesion intervention. The use of whole human fetal membranes or amnion alone in surgery has primarily developed to aid the repair of surface epithelial defects in the skin, eye, abdominal wall and peritoneum. HAM grafting has not been very popular in the field of obstetrics and gynaecology; its clinical use is limited to as a graft in forming an artificial vagina or as a barrier to prevent postoperative intra-abdominal adhesion formation, or finally as a biological dressing following radical vulvectomies and groin dissections (Amer 2006).
How the intervention might work
The hypothetical underlying mechanisms of infertility associated with IUAs are obstruction of sperm transport into the cervix, impaired embryo migration within the uterine cavity or failure of embryo implantation due to endometrial insufficiency (Deans 2010). The ideal anti-adhesion adjunctive therapy following operative hysteroscopy would be the application of a biologically active mechanical separator that achieves the suppression of intrauterine adhesion formation and promotes the healing of the endometrium. The bulk of evidence on how the different interventions might work is derived from animal studies, largely in rodents and not in validated animal models for the study of human reproduction (D'Hooghe 2009), or observational studies.
Intrauterine contraceptive device (IUD) or Foley catheter balloon
The use of an IUD (13 observational studies) or a Foley catheter balloon (eight observational studies) (Deans 2010) is often recommended following the hysteroscopic treatment of IUAs or septoplasty, to act as a physical barrier separating the opposing walls of the uterine cavity. The type of IUD may be important; copper-containing IUDs provoke an inflammatory reaction, probably with detrimental effects, whereas T-shaped IUDs might have too small a surface area to be truly effective in providing an efficient physical barrier. The loop IUD (for example Lippes loop) is generally considered the IUD of choice when treating IUAs; it is, however, no longer available in many countries (Kodaman 2007). One clinical controlled trial (Orhue 2003) compared the use of a Foley catheter balloon for 10 days (N = 59) versus the insertion of an IUD during a three month period (N = 51); the fertility rates were poor in both the IUD group (20/59 or 34%) and the Foley catheter group (14/51 or 28%).
Many studies recommend the use of a cyclical estrogen and progestogen treatment regimen following the hysteroscopic treatment of IUAs to promote the regeneration of the endometrium (Deans 2010). Various regimens have been proposed consisting of estrogen (for example a typical daily dose of 2.5 mg of conjugated equine estrogen twice daily for 30 days) with or without a progestin (for example 10 mg medroxyprogesterone acetate for 10 days) (Kodaman 2007). No comparative studies have been performed on dosage, administration or combination of hormones (Deans 2010). In a randomized controlled trial (Farhi 1993) 60 women undergoing dilation and curettage during the first trimester of pregnancy were allocated to receive estrogen and progestin or no treatment. Women in the intervention group had a significantly thicker endometrium (8.4 versus 6.7 mm, P = 0.02) compared with the control group. The authors concluded that postoperative hormone treatment may be beneficial for intrauterine adhesion prevention following surgical trauma to the uterine cavity. Nevertheless, no data were available on pregnancy outcome or intrauterine adhesion recurrence (Farhi 1993). A systematic review of observational studies concluded that hormonal therapy, particularly estrogen therapy, may be beneficial to women with IUAs but as an adjunctive therapy combined with other anti-adhesion strategies (Johary 2013).
The use of the biodegradable gel surgical barriers is based on the principle of keeping the adjacent wound surfaces mechanically separate (Renier 2005). Several preclinical studies in various animal models have demonstrated the effectiveness of both ACP (Belluco 2001; Binda 2007; Binda 2009; Binda 2010; De Iaco 1998; Koçak 1999; Shamiyeh 2007; Wallwiener 2006) and HA-CMC gels (Leach 1998 ; Schonman 2008) or HA-CMC membranes (Kelekci 2004; Rajab 2010) for preventing postsurgical adhesions. Other preclinical studies in animal models suggest that HA gel remains in situ for more than five to six days (Laurent 1992; Nimrod 1992). Similarly, animal studies demonstrate the persistence of HA-CMC for about seven days after its application (Diamond 1988). The exact mechanisms by which ACP and HA-CMC are able to reduce adhesion reformation are not well known but may be related to 'hydroflotation' or 'siliconizing' effects. One French clinical controlled trial (N = 54 women) compared the application of ACP gel (N = 30) versus no gel at the end of an operative hysteroscopic procedure for treating myomas, polyps, uterine septa or IUAs; there were no statistically significant differences for the rate of adhesion formation between comparison groups, nor for the mean adhesion scores or the severity of the adhesions (Ducarme 2006). There were no data on the reproductive outcome.
Human amnion membrane grafting
The preclinical data on the effectiveness of HAM grafting in different animal models present conflicting results. One trial (Szabo 2002) demonstrates a beneficial effect in preventing de novo adhesions whereas according to two other animal studies (Arora 1994; Badawy 1989) HAM grafting fails to prevent de novo adhesion formation. One observational study reports data on the use of a fresh amnion graft over an inflated Foley catheter to prevent recurrence of intrauterine adhesions after hysteroscopic lysis in 25 women with moderate to severe Asherman syndrome. Minimal adhesion reformation was demonstrated in 48% of the study participants with severe adhesions. The authors conclude that HAM grafting might be promising as an adjunctive therapy following hysteroscopic adhesiolysis; it acts as a biologically active mechanical barrier suppressing adhesion formation and promoting endometrial healing (Amer 2006). A fresh HAM graft preserves its viability for 21 days following its application in the pelvic cavity (Trelford Sauder 1977). In addition to being an anatomical barrier HAM may promote the regeneration of epithelium by acting as a basement membrane substrate; HAM may also facilitate the migration of epithelial cells, reinforce the adhesion of the basal epithelium, promote epithelial cell differentiation (Meller 1999) and prevent cellular apoptosis (Hori 2006). Human amnion epithelial cells produce factors or create a microenvironment for effective tissue repair and endometrial regeneration, possibly by stimulating endogenous stem cells (Padykula 1991).
Why it is important to do this review
At present it is not clear whether the use of anti-adhesion therapies after operative hysteroscopy might be beneficial for the outcomes of pregnancy or live birth. Answering this question is the main objective of this Cochrane review. Moreover, little is known about the relative contribution of different anti-adhesion strategies in increasing reproductive benefit in women wishing to conceive following operative hysteroscopy; this head to head comparison of the alternative anti-adhesion interventions is a secondary objective of the present research.
Adhesions may cause infertility, abdominal pain, or bowel obstruction. The health burden associated with these three clinical problems is substantial (DeCherney 1997; diZerega 1994; Renier 2005). The total cost of adhesion-related morbidity in the US Health Care system exceeds $ 1 billion annually (Baakdah 2005). One trial in the domain of gynaecologic oncology (Bristow 2007) evaluated the cost-effectiveness of using a HA-CMC anti-adhesion barrier compared to routine care, in which no adhesion prevention measures were taken, through a decision analysis model in the setting of women undergoing radical hysterectomy and pelvic lymphadenectomy for stage IB cervical cancer. The authors concluded that given a conservative set of clinical and economic assumptions, an adhesion prevention strategy utilizing a HA-CMC barrier in women undergoing radical hysterectomy for Stage IB cervical cancer might be cost-effective from both the perspective of society as a whole and that of a third party payer. To the best of our knowledge there are no cost-effectiveness studies on adhesion prevention after operative hysteroscopy in an infertile population; the evidence retrieved from the present research could be the basis for further economical studies of different anti-adhesion treatments. This is another secondary objective of the present review.
Infertility, the inability to conceive after a defined period of unprotected intercourse, is an often neglected aspect of reproductive health worldwide. The official development of assistance for reproductive health care and family planning remains low worldwide despite an increasing absolute number of couples affected by infertility, from 42.0 million in 1990 to 48.5 million in 2010 (Mascarenhas 2012). Therefore the World Health Organization (WHO) has recognized reproductive health as a priority global health area; the target for the United Nations Millennium Development Goal 5B is to provide universal access to reproductive health by 2015 (http://www.un.org/millenniumgoals/maternal.shtml).